Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Dry, Jonathan R., Pavey, Sandra, Pratilas, Christine A., Harbron, Chris, Runswick, Sarah, Hodgson, Darren, Chresta, Christine, McCormack, Rose, Byrne, Natalie, Cockerill, Mark, Graham, Alexander, Beran, Garry, Cassidy, Andrew, Haggerty, Carolyn, Brown, Helen, Ellison, Gillian, Dering, Judy, Taylor, Barry S., Stark, Mitchell, Bonazzi, Vanessa, Ravishankar, Sugandha, Packer, Leisl, Xing, Feng, Solit, David B., Finn, Richard S., Rosen, Neal, Hayward, Nicholas K., French, Tim, & Smith, Paul D. (2010) Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Research, 70(6), pp. 2264-2273.

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Abstract

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Impact and interest:

110 citations in Scopus
100 citations in Web of Science®
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ID Code: 76310
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Keywords: 5 (4 bromo 2 chloroanilino) 4 fluoro 1 methyl 1h benzimidazole 6 carbohydroxamic acid 2 hydroxyethyl ester; enzyme inhibitor; messenger RNA; mitogen activated protein kinase kinase; phosphatidylinositol 3 kinase; article; breast tumor; cancer model; colon
DOI: 10.1158/0008-5472.CAN-09-1577
ISSN: 1538-7445
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL BIOCHEMISTRY AND METABOLOMICS (110100)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 23 Sep 2014 23:11
Last Modified: 22 Jun 2017 15:01

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